Legacy benefits of blood pressure treatment on cardiovascular events are primarily mediated by improved blood pressure variability: the ASCOT trial.

BACKGROUND AND AIMS: Visit-to-visit systolic blood pressure variability (BPV) is an important predictor of cardiovascular (CV) outcomes. The long-term effect of a period of blood pressure (BP) control, but with differential BPV, is uncertain. Morbidity and mortality follow-up of UK participants in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm has been extended for up to 21 years to determine the CV impact of mean systolic blood pressure (SBP) control and BPV during the trial, and amongst those allocated to amlodipine- and atenolol-based treatment. METHODS: Eight thousand five hundred and eighty hypertensive participants (4305 assigned to amlodipine ± perindopril-based and 4275 to atenolol ± diuretic-based treatment during the in-trial period (median 5.5 years) were followed for up to 21 years (median 17.4 years), using linked hospital and mortality records. A subgroup of participants (n = 2156) was followed up 6 years after the trial closure with a self-administered questionnaire and a clinic visit. In-trial mean SBP and standard deviation of visit-to-visit SBP as a measure of BPV, were measured using >100 000 BP measurements. Cox proportional hazard models were used to estimate the risk [hazard ratios (HRs)], associated with (i) mean with SBP and BPV during the in-trial period, for the CV endpoints occurring after the end of the trial and (ii) randomly assigned treatment to events following randomization, for the first occurrence of pre-specified CV outcomes. RESULTS: Using BP data from the in-trial period, in the post-trial period, although mean SBP was a predictor of CV outcomes {HR per 10 mmHg, 1.14 [95% confidence interval (CI) 1.10-1.17], P < .001}, systolic BPV independent of mean SBP was a strong predictor of CV events [HR per 5 mmHg 1.22 (95% CI 1.18-1.26), P < .001] and predicted events even in participants with well-controlled BP. During 21-year follow-up, those on amlodipine-based compared with atenolol-based in-trial treatment had significantly reduced risk of stroke [HR 0.82 (95% CI 0.72-0.93), P = .003], total CV events [HR 0.93 (95% CI 0.88-0.98), P = .008], total coronary events [HR 0.92 (95% CI 0.86-0.99), P = .024], and atrial fibrillation [HR 0.91 (95% CI 0.83-0.99), P = .030], with weaker evidence of a difference in CV mortality [HR 0.91 (95% CI 0.82-1.01), P = .073]. There was no significant difference in the incidence of non-fatal myocardial infarction and fatal coronary heart disease, heart failure, and all-cause mortality. CONCLUSIONS: Systolic BPV is a strong predictor of CV outcome, even in those with controlled SBP. The long-term benefits of amlodipine-based treatment compared with atenolol-based treatment in reducing CV events appear to be primarily mediated by an effect on systolic BPV during the trial period.

Polypill with or without Aspirin in Persons without Cardiovascular Disease.

BACKGROUND: A polypill comprising statins, multiple blood-pressure-lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease. METHODS: Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly. We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed. RESULTS: A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo. The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10). The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the double-placebo group (hazard ratio, 0.69; 95% CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups. CONCLUSIONS: Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk. (Funded by the Wellcome Trust and others; TIPS-3 ClinicalTrials.gov number, NCT01646437.).

Modeling Free Nitrous Acid Inhibition on the Removal of Nitrogen and Atenolol during Sidestream Partial Nitritation Processes.

Sidestream serves as an important reservoir collecting pharmaceuticals from sludge. However, the knowledge on sidestream pharmaceutical removal is still insufficient. In this work, atenolol biodegradation during sidestream partial nitritation (PN) processes characterized by high free nitrous acid (FNA) accumulation was modeled. To describe the FNA inhibition on ammonia oxidation and atenolol removal, Vadivelu-type and Hellinga-type inhibition kinetics were introduced into the model framework. Four inhibitory parameters along with four biodegradation kinetic parameters were calibrated and validated separately with eight sets of batch experimental data and 60 days' PN reactor operational data. The developed model could accurately reproduce the dynamics of nitrogen and atenolol. The model prediction further revealed that atenolol biodegradation efficiencies by ammonia-oxidizing bacteria (AOB)-induced cometabolism, AOB-induced metabolism, and heterotrophic bacteria-induced biodegradation were 0, ∼ 60, and ∼35% in the absence of ammonium and FNA; ∼ 14, ∼ 29, and ∼28% at 0.03 mg-N L-1 FNA; and 7, 15, and 5% at 0.19 mg-N L-1 FNA. Model simulation showed that the nitritation efficiency of ∼99% and atenolol removal efficiency of 57.5% in the PN process could be achieved simultaneously by controlling pH at 8.5, while 89.2% total nitrogen and 57.1% atenolol were removed to the maximum at pH of 7.0 in PN coupling with the anammox process. The pH-based operational strategy to regulate FNA levels was mathematically demonstrated to be effective for achieving the simultaneous removal of nitrogen and atenolol in PN-based sidestream processes.

ß-Adrenoceptor blockade can augment the torsadogenic action of risperidone.

Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit IKr, but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that dl-sotalol (ß-adrenoceptor blockade plus IKr inhibition) induced TdP three times more frequently than d-sotalol (IKr inhibition alone). Since risperidone can block α1-adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on ß-adrenoceptor might protect the heart from its IKr inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after ß-adrenoceptor blocker atenolol infusion with monitoring J-Tpeak and Tpeak-Tend, which are proarrhythmic surrogate markers of "substrate" and "trigger" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-Tpeak and Tpeak-Tend in animals that induced TdP. These findings indicate that ß-adrenoceptor blockade can diminish repolarization reserve to augment risperidone's torsadogenic potential, thus advising caution when using ß-adrenoceptor blockers in patients with IKr inhibition-linked labile repolarization.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Qualification of In Vitro Dissolution Absorption System 2 (IDAS2) with Caco-2 and MDCK Cell Monolayers: Dose Sensitivity Study Using BCS Class I and III Drugs.

This study aimed to validate the In vitro Dissolution Absorption System 2 (IDAS2) containing a biological barrier of Caco-2 or Madin-Darby canine kidney (MDCK) cell monolayer through dose sensitivity studies. Metoprolol and propranolol were selected as Biopharmaceutics Classification System (BCS) Class I model drugs, and atenolol as a Class III model drug. The IDAS2 is comprised of a dissolution vessel (500 mL) and two permeation chambers (2 × 8.0 mL) mounted with Caco-2 or MDCK cell monolayer. One or two immediate-release tablet(s) of the model drug were added to the dissolution vessel, and the time profiles of dissolution and permeation were observed. Greater than 85% of metoprolol and propranolol (tested at two dosing concentrations) were dissolved by 15 min, and all drugs were fully dissolved by 30 min. All three drugs were more permeable across Caco-2 cells than MDCK cells with a linear increase in permeation across both cells at both dose concentrations. Thus, the dose sensitivity of the IDAS2 was demonstrated using both cell barriers. These results indicate a successful qualification of IDAS2 for the development/optimization of oral formulations and that MDCK cells can be utilized as a surrogate for Caco-2 cells.

Effect of ultra-high-density polyethylene microplastic on the sorption and biodegradation of organic micropollutants.

Microplastics and organic micropollutants are two emerging contaminants that interact with each other in environmental and engineered systems. Sorption of organic micropollutants, such as pharmaceuticals, pesticides and industrial compounds, to microplastics can modify their bioavailability and biodegradation. The present study investigated the capacity of ultra-high density polyethylene particles (125 µm in diameter), before and after aging, to sorb 21 organic micropollutants at different environmentally relevant concentration. Furthermore, the biodegradation of these organic micropollutants by a biofilm microbial community growing on the microplastic surface was compared with the biodegradation by a microbial community originating from activated sludge. Among all tested organic micropollutants, propranolol (70%), trimethoprim (25%) and sotalol (15%) were sorbed in the presence of polyethylene particles. Growth of a biofilm on the polyethylene particles had a beneficial effect on the sorption of bromoxynil, caffeine and chloridazon and on the biodegradation of irbesartan, atenolol and benzotriazole. On the other hand, the biofilm limited the sorption of trimethoprim, propranolol, sotalol and benzotriazole and the biodegradation of 2,4-D. These results showed that ultra-high density polyethylene particles can affect both in a positive and negative way for the abiotic and biotic removal of organic micropollutants in wastewater. This project highlights the need for further investigation regarding the interaction between microplastics and organic micropollutants in the aquatic environment.

Eco-friendly simultaneous estimation of atenolol and losartan potassium in spiked human plasma via synchronous fluorescence with sustainability assessment.

A green, sensitive, and fast spectrofluorimetric technique for the simultaneous determination of atenolol (ATN) and losartan potassium (LSR) was developed. The proposed technique relied on the implementation of a first derivative synchronous fluorescence spectroscopy for the determination of the investigated drugs simultaneously without pretreatment procedures. The synchronous fluorescence of both drugs was measured in methanol at Δλ of 100 nm, and the first derivative peak amplitudes (1D) were measured at 321 nm for ATN and 348 nm for LSR, each at the zero-crossing point of the other. The method was rectilinear over the concentration ranges of 100-1000 ng/mL and 50-500 ng/mL for ATN and LSR, respectively. The proposed technique was successfully applied for the determination of the studied drugs in their laboratory-prepared mixture and pharmaceutical formulations, demonstrating high mean recoveries of 100.54% for ATN and 100.62% for LSR, without interference from common excipients. The results were in good agreement with those obtained by the comparison method. Three recent greenness assessment tools, the Eco-Scale tool, the Green Analytical Procedure Index (GAPI) metric, and the Analytical GREEnness metric approach, were employed to affirm the greenness of the proposed method. The developed method was proven to be eco-friendly.

Quantitative analysis of solid dosage forms of Atenolol by Raman spectroscopy.

OBJECTIVE: To develop a Raman spectroscopy-based analytical model for quantification of solid dosage forms of active pharmaceutical ingredient (API) of Atenolol.Significance: For the quantitative analysis of pharmaceutical drugs, Raman Spectroscopy is a reliable and fast detection method. As part of this study, Raman Spectroscopy is explored for the quantitative analysis of different concentrations of Atenolol. METHODS: Various solid-dosage forms of Atenolol were prepared by mixing API with excipients to form different solid-dosage formulations of Atenolol. Multivariate data analysis techniques, such as Principal Component Analysis (PCA) and Partial least square regression (PLSR) were used for the qualitative and quantitative analysis, respectively. RESULTS: As the concentration of the drug increased in formulation, the peak intensities of the distinctive Raman spectral characteristics associated with the API (Atenolol) gradually increased. Raman spectral data sets were classified using PCA due to their distinctive spectral characteristics. Additionally, a prediction model was built using PLSR analysis to assess the quantitative relationship between various API (Atenolol) concentrations and spectral features. With a goodness of fit value of 0.99, the root mean square errors of calibration (RMSEC) and prediction (RMSEP) were determined to be 1.0036 and 2.83 mg, respectively. The API content in the blind/unknown Atenolol formulation was determined as well using the PLSR model. CONCLUSIONS: Based on these results, Raman spectroscopy may be used to quickly and accurately analyze pharmaceutical samples and for their quantitative determination.

Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Synthesis of Enantiopure (S)-Atenolol by Utilization of Lipase-Catalyzed Kinetic Resolution of a Key Intermediate.

(S)-Atenolol ((S)-2-(4-(2-Hydroxy-3-(isopropylamino)propoxy)phenyl)acetamide) has been synthesized in >99% enantiomeric excess (ee) with the use of Candida antarctica lipase B from Syncozymes (Shanghai, China), in a kinetic resolution of the corresponding racemic chlorohydrin. A catalytic amount of base was used in deprotonation of the phenol building block. The enantiopurity of the chlorohydrin building block remained unchanged upon subsequent amination to yield the final drug. All four steps in the synthesis protocol have been optimized compared to previously reported methods, which makes this new protocol more sustainable and in accordance with green chemistry principles. The overall yield of (S)-atenolol was 9.9%, which will be further optimized.

Supramolecular Interaction of Atenolol and Propranolol with ß-Cyclodextrin Spectroscopic Characterization and Analytical Application.

Atenolol (ATE) and propranolol (PRO) inclusion complexes with ß-cyclodextrin have been investigated in aqueous solution. The aqueous solution was examined and characterized using UV-vis, fluorescence spectroscopy, and 1H NMR. The physical mixture was characterized using FTIR. The existence of inclusion complexes is confirmed by observing changes in spectroscopic properties. The ATE complex with ß-CD exhibited an interaction as host and (ß-CD) as a guest in a 1:1 ratio, with an inclusion constant K of 2.09 × 10-3 µM-1, as determined by the typical double-reciprocal graphs. Similarly, the PRO complex with ß-CD exhibited an interaction as host and (ß-CD) guest in 1:1 and 1:2 stoichiometry at the same time; the inclusion constants were K1 = 5.80 × 10-5 µM-1 and K2 = 4.67 × 10-8 µM-1, as determined by typical double-reciprocal graphs. The variables influencing the formation of the inclusion complexes were investigated and optimized. Based on the enhancement in fluorescence intensity due to the formation of inclusion complexes, spectrofluorometric methods were developed and validated for determination of each drug's pharmaceutical formulation. The quantification of the fluorescence intensity for ATE and PRO was conducted at λex/λem 226/302 nm and λex/λem 231/338 nm, respectively. Under the optimal reaction circumstances, linear relationships with good correlation coefficients of 0.9918 and 0.99 were found in the concentration ranges of 0.3-1.7 µM, and 0.1-1.1 µM for ATE and PRO, respectively. The limits of detection (LODs) were found to be 0.13 and 0.01 µM for ATE and PRO, respectively. The suggested approach was effectively applied to the analysis of both drugs' pharmaceutical formulations.

Development of a High-Field "Brick" Mass Spectrometer with Extended Mass Range and Capable of Characterizing Native Proteins.

One of the main challenges of analyzing intact proteins on an ion trap mass spectrometer is the mass range limitation, especially for miniature mass spectrometers. In this study, a high-field frequency scanning ion trap miniature mass spectrometer, namely the high-field "Brick" mass spectrometer, was developed to analyze intact proteins. A high-voltage broadband radio frequency (rf) amplifier was designed with a maximum output of 900 Vp-p over a frequency range of 130-700 kHz. Compared to the 600 Vp-p rf amplifier equipped in the conventional "Brick" mass spectrometer, the mass range of the instrument could be extended from 2000 to over 8000 Th. Sensitivity and mass resolution for native protein analyses were also evaluated and compared. Various proteins as well as their mixtures were analyzed on the high-field "Brick" mass spectrometer. The noncovalent interaction between protein-ligand complexes, lysozyme with triN-acetylchitotriose, was also analyzed. In addition, a hybrid ion scan mode was explored to further expand the mass range of the instrument at both low- and high-mass ends. In the hybrid ion scan mode, both rf frequency and amplitude were tuned, and a mass range from 100 to 12,000 Th was realized. As a result, both small drugs and proteins could be analyzed in a single mass scan. As proof-of-concept demonstrations, a mixture of atenolol and bovine serum albuminand oligomers of transferrin were analyzed.

Insights into degradation of pharmaceutical pollutant atenolol via electrochemical advanced oxidation processes with modified Ti4O7 electrode: Efficiency, stability and mechanism.

A novel active Ce-doped Ti4O7 (Ti/Ti4O7-Ce) electrode was prepared and evaluated for improvement of the refractory pollutants degradation efficiency in Electrochemical advanced oxidation processes (EAOPs). The results showed that the addition of Ce in Ti/Ti4O7 electrode leading to great impact on •OH generation rate and electrode stability compared to pristine Ti/Ti4O7 electrode. Ti/Ti4O7-Ce electrode presented efficient oxidation capacity for pharmaceutical pollutant atenolol (ATL) in EAOPs, which could be attributed to the improvement of indirect oxidation mediated by electro-generated •OH, as the amount of •OH production was 16.5% higher than that in Ti/Ti4O7 within 120 min. The operational conditions greatly influenced the ATL degradation. The degradation efficiency of ATL increased as the current density, the degradation efficiency reached 100% under pH 4, but it just removed 81% of ATL under pH 10 after 120 min treatment. Results also suggested that the inhibiting effect from the ATL degradation was mostly associated with the decreased oxidation capacity induced by water hardness and natural organic matter (NOM). It displayed a satisfactory durability after 40 cycles of experimental detections in this research. The results of study suggested that Ti/Ti4O7-Ce was a promising electrode for the efficient degradation of PPCPs-polluted wastewater and provided constructive suggestion for the refractory pollutants of EAOPs.

Analyzing microbial communities and their biodegradation of multiple pharmaceuticals in membrane bioreactors.

Pharmaceuticals are of concern to our planet and health as they can accumulate in the environment. The impact of these biologically active compounds on ecosystems is hard to predict, and information on their biodegradation is necessary to establish sound risk assessment. Microbial communities are promising candidates for the biodegradation of pharmaceuticals such as ibuprofen, but little is known yet about their degradation capacity of multiple micropollutants at higher concentrations (100 mg/L). In this work, microbial communities were cultivated in lab-scale membrane bioreactors (MBRs) exposed to increasing concentrations of a mixture of six micropollutants (ibuprofen, diclofenac, enalapril, caffeine, atenolol, paracetamol). Key players of biodegradation were identified using a combinatorial approach of 16S rRNA sequencing and analytics. Microbial community structure changed with increasing pharmaceutical intake (from 1 to 100 mg/L) and reached a steady-state during incubation for 7 weeks on 100 mg/L. HPLC analysis revealed a fluctuating but significant degradation (30-100%) of five pollutants (caffeine, paracetamol, ibuprofen, atenolol, enalapril) by an established and stable microbial community mainly composed of Achromobacter, Cupriavidus, Pseudomonas and Leucobacter. By using the microbial community from MBR1 as inoculum for further batch culture experiments on single micropollutants (400 mg/L substrate, respectively), different active microbial consortia were obtained for each single micropollutant. Microbial genera potentially responsible for degradation of the respective micropollutant were identified, i.e. Pseudomonas sp. and Sphingobacterium sp. for ibuprofen, caffeine and paracetamol, Sphingomonas sp. for atenolol and Klebsiella sp. for enalapril. Our study demonstrates the feasibility of cultivating stable microbial communities capable of degrading simultaneously a mixture of highly concentrated pharmaceuticals in lab-scale MBRs and the identification of microbial genera potentially responsible for the degradation of specific pollutants. KEY POINTS: • Multiple pharmaceuticals were removed by stable microbial communities. • Microbial key players of five main pharmaceuticals were identified.

Long-term neurocognitive functioning of children treated with propranolol or atenolol for infantile hemangioma.

The purpose of this study was to compare long-term neurocognitive functioning (working memory, processing speed, and attention) between children who had been treated with either propranolol or atenolol for infantile hemangioma during infancy. All eligible children (n = 158) aged 6 years or older and treated with propranolol or atenolol as infants were invited to participate in this two-center cross-sectional study. The primary outcome was the Wechsler Intelligence Scale for Children-V Cognitive Proficiency Index (CPI), a measure of working memory, processing speed, and attention. Secondary outcomes were general intelligence, auditory, visuospatial, and narrative memory, as well as executive functioning and sleep. A total of 105 children, of whom 36 had been treated with propranolol (age 6.0-11.8 years, follow-up time 1.6-9.7 years, 19% male) and 69 had been treated with atenolol (age 6.9-9.7 years, follow-up time 4.5-8.4 years, 19% male), were analyzed. The CPI and other neurocognitive outcomes did not differ between the propranolol and atenolol groups and were in line with general population test norms. Post hoc analyses revealed lower CPI scores for males, both compared to participating females (10.3 IQ points, medium effect size) and compared to matched test norms (12.4 IQ points, medium effect size). CONCLUSIONS:  Long-term neurocognitive functioning did not differ between children treated with propranolol and those treated with atenolol for IH. Overall, propranolol and atenolol appear to be safe treatments for IH regarding long-term neurocognitive functioning. The substantially lower CPI scores in males warrant further investigation. TRIAL REGISTRATION:  Netherlands Trial Register, NL7703 https://www.trialregister.nl/trial/7703 What is Known: • Infants with infantile hemangioma are effectively treated with propranolol or atenolol. • Parents and professionals are concerned about long-term neurocognitive effects. WHAT IS NEW: • No long-term (≥ 6 years) differences in neurocognitive functioning were found between children treated with propranolol or atenolol. • Males treated with beta-blockers had substantially lower IQ scores than treated females and males from the general population, which is a matter of concern and should be considered when evaluating the risk/benefit ratio in less severe forms of infantile hemangioma.

Pediatric Heart Network Trial of Losartan vs. Atenolol in Children and Young Adults with Marfan Syndrome: Impact on Prescription Practices.

The Pediatric Heart Network (PHN) trial showed similar efficacy of ß-blockers (BB) and angiotensin receptor blockers (ARB) for aortic root dilation in Marfan syndrome, but the impact on prescription practices is unknown. We hypothesized BB and ARB prescriptions would increase after the trial results were published (2014). Prescription data (2007-2016) were obtained from outpatient encounters (IBM Marketscan) for Marfan syndrome patients (6 months-25 years old). Excluding 2014 as a washout period, we analyzed two intervals: 2007-2013 and 2015-2016. Medication categories included BB, ARB, angiotensin converting enzyme inhibitors (ACEI), combination (BB/ARB and/or BB/ACEI), and no drug. Interrupted time-series analysis assessed immediate level change after publication and change in slope for the trend pre- and post-publication. Odds ratios (OR) and 95% confidence intervals from logistic regressions and generalized estimating equation methods accounted for correlation of prescriptions within patients. In 1499 patients (age 14.1 ± 6.1 years, 59% female) seen 2007-2013, BB trended lower [OR 0.91 (0.89, 0.93), p < 0.001] and ARB trended higher [OR 1.12 (1.07, 1.18), p < 0.001], while combination, ACEI, and no drug remained stable. This trend persisted, but was not significant, for BB [OR 0.54 (0.27, 1.08), p = 0.37] and ARB [OR 1.91 (0.55, 6.69), p = 0.31] in 2015-2016. Combination, ACEI, and no drug remained similar. In short term follow-up, changes in prescription practices following publication of the PHN trial were not statistically significant. This may be due to a change seen prior to publication with early adoption of ARBs that was maintained after confirmation of their effectiveness.

Zeolitic imidazolate framework-67-modified open-tubular column with cyclodextrin for enantioseparation in capillary electrochromatography.

The histidine-modified zeolitic imidazolate framework [His-ZIF-67] was prepared with the histidine, 2-methylimidazole, and Co2+ under ambient temperature. His-ZIF-67 was bonded via a glycidyl methacrylate copolymer to the internal surface of capillary and then functionalized with the NH2 -ß-cyclodextrin (NH2 -ß-CD). The materials were characterized by field emission scanning electron microscopy, high-resolution transmission electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, N2 adsorption-desorption isotherm, X-ray diffraction, and X-ray photoelectron spectroscopy. In comparison with the NH2 -ß-CD@capillary, the NH2 -ß-CD@His-ZIF-67@capillary-coated column shows significantly enhanced resolution for chiral molecules. The NH2 -ß-CD@His-ZIF-67@capillary column achieved the baseline separation of amlodipine and metoprolol (the resolution of amlodipine: 1.70; metoprolol: 1.50) and the partial separation of atenolol and propranolol (the resolution of atenolol: 1.03; propranolol: 0.60). These were attributed to the histidine modification and the features of ZIF-67, including an excellent surface area and the abundant porosity. The pH and proportion of organic modifier in the buffer were crucial for enantioseparation performance and were evaluated in detail. The fabricated NH2 -ß-CD@His-ZIF-67@capillary-coated column showed good stability and repeatability (relative standard deviation <6.3%). The molecular modeling with AutoDock and grand canonical ensemble was carried out to evaluate the interactions between chiral stationary phase and racemic drugs.

Pharmaceutical Biotransformation is Influenced by Photosynthesis and Microbial Nitrogen Cycling in a Benthic Wetland Biomat.

In shallow, open-water engineered wetlands, design parameters select for a photosynthetic microbial biomat capable of robust pharmaceutical biotransformation, yet the contributions of specific microbial processes remain unclear. Here, we combined genome-resolved metatranscriptomics and oxygen profiling of a field-scale biomat to inform laboratory inhibition microcosms amended with a suite of pharmaceuticals. Our analyses revealed a dynamic surficial layer harboring oxic-anoxic cycling and simultaneous photosynthetic, nitrifying, and denitrifying microbial transcription spanning nine bacterial phyla, with unbinned eukaryotic scaffolds suggesting a dominance of diatoms. In the laboratory, photosynthesis, nitrification, and denitrification were broadly decoupled by incubating oxic and anoxic microcosms in the presence and absence of light and nitrogen cycling enzyme inhibitors. Through combining microcosm inhibition data with field-scale metagenomics, we inferred microbial clades responsible for biotransformation associated with membrane-bound nitrate reductase activity (emtricitabine, trimethoprim, and atenolol), nitrous oxide reduction (trimethoprim), ammonium oxidation (trimethoprim and emtricitabine), and photosynthesis (metoprolol). Monitoring of transformation products of atenolol and emtricitabine confirmed that inhibition was specific to biotransformation and highlighted the value of oscillating redox environments for the further transformation of atenolol acid. Our findings shed light on microbial processes contributing to pharmaceutical biotransformation in open-water wetlands with implications for similar nature-based treatment systems.

Free Nitrous Acid Inhibits Atenolol Removal during the Sidestream Partial Nitritation Process through Regulating Microbial-Induced Metabolic Types.

Limited studies have attempted to evaluate pharmaceutical removal during the sidestream partial nitritation (PN) process. In this work, atenolol biodegradation by PN cultures was investigated by maintaining ammonium and pH at different levels. For the first time, free nitrous acid (FNA), other than ammonium, pH, and free ammonia, was demonstrated to inhibit atenolol removal, with biodegradation efficiencies of ∼98, ∼67, and ∼28% within 6 days at average FNA levels of 0, 0.03, and 0.19 mg-N L-1, respectively. Ammonia-oxidizing bacteria (AOB)-induced metabolism was predominant despite varying FNA concentrations. In the absence of ammonium/FNA, atenolol was mostly biodegraded via AOB-induced metabolism (65%) and heterotroph-induced metabolism (33%). AOB-induced metabolism was largely inhibited (down to 29%) at 0.03 mg-N L-1 FNA, while ∼27 and ∼11% were degraded via heterotroph-induced metabolism and AOB-induced cometabolism, respectively. Higher FNA (0.19 mg-N L-1) substantially reduced atenolol biodegradation via heterotroph-induced metabolism (4%), AOB-induced metabolism (16%), and AOB-induced cometabolism (8%). Newly identified products and pathways were related to metabolic types and FNA levels: (i) deamination and decarbonylation (AOB-induced cometabolism, 0.03 mg-N L-1 FNA); (ii) deamination from atenolol acid (heterotrophic biodegradation); and (iii) nitro-substitution (reaction with nitrite). This suggests limiting FNA to realize simultaneous nitrogen and pharmaceutical removal during the sidestream process.